Features: Racing Evolution

Racing Evolution: A new strategy for antibiotic synthesis

By Alan Yang

When it comes to antibiotics, the pace of our discoveries often lags far behind the rate of bacterial evolution. Recent detections of superbugs resistant to even our last lines of antibiotic defense suggest that antibiotics are changing from miraculous inventions to useless relics (1). The implications are terrifying. Without new antibiotics, banished pestilences can rear their ugly heads again, and even mundane infections can become life-threatening.

We need new antibiotics, but it’s not easy to make them. Many current antibiotics were made by harvesting natural products with antimicrobial properties from fungi or bacteria and then modifying them to make drugs that can be used in humans. To make these modifications, scientists typically employ an approach known as semi-synthesis: they attach different chemical groups at specific sites on the natural product to change its pharmacological properties. This approach, however, is laborious and limited in scope because natural products are complex molecules that often cannot be easily modified with high specificity. For instance, the macrolide class of antibiotics–used to treat diseases ranging from STIs to skin infections–are all derived from the natural product erythromycin, which was first harvested from soil samples in 1949. But there are only so many ways one can efficiently modify erythromycin. This means that it is difficult to develop new macrolide antibiotics to overcome antibiotic resistance.

However, Professor Andrew G. Myers’s lab at Harvard University has figured out a way to get around both the tediousness and the limitations of semi-synthesis.

In a recent paper in Nature, they reported a synthetic strategy based on eight modifiable “chemical building blocks” that can be combined to make an exponential variety of macrolide antibiotics in high quantities (2). These chemical building blocks are small molecular fragments that, when combined in a particular series of steps, react with each other to form a larger macrolide molecule. Unlike semi-synthetic strategies, therefore, Myers’s approach allows for the practical and complete synthesis of a diverse range of macrolides without having to start from erythromycin.

Without new antibiotics, banished pestilences can rear their ugly heads again, and even mundane infections can become life-threatening.

Because it eliminates the need to work with a natural product, Myers’s strategy drastically reduces the difficulty of producing new drugs. Semi-synthesis relies on making highly specific chemical modifications to erythromycin, a task that requires many arduous synthetic maneuvers. Myers’s “building block” strategy, however, contains fewer than a dozen steps. It is also highly robust: it works well even when the initial building blocks contain modifications, as long as the overall structures of the building blocks are preserved. This versatility means that Myers’s procedure can be used to generate new macrolides with a wide range of chemical flavors.

Using their published strategy, Myers’s lab has already synthesized over 300 macrolides, many of which inhibit growth in bacteria that are resistant to erythromycin and other macrolides already on the market.

Myers’s strategy therefore demonstrates a practical, simple, and highly versatile method of synthesizing macrolides. Strategies like these might make antibiotic development more attractive to pharmaceutical companies, which have been increasingly reluctant to invest in antibiotic development (3). More importantly, this strategy might help us catch up with bacterial evolution and overcome resistance as it arises in the future.

References

Sun, L.H., Dennis, B. (2016, May 27). The Superbug that doctors have been dreading just reached the U.S. The Washington Post, Retrieved from https://www.washingtonpost.com/.